Project Summary/Abstract This is a basic research study to analyze the earliest corneal changes induced by an obesogenic diet. We are attempting to understand the pathogenesis of an important corneal condition before it reaches the far advanced stages of the metabolic syndrome. There is a heightened concern given the epidemic of obesity in children. We will use diet-induced obesity and full thickness corneal epithelial abrasion in C57BL/6J mice for studies in vivo. The pathogenic effect of a diet is not simply determined by the nutritive content or quantity of the food source, but includes the timing of food intake as shown by recent investigations. Our studies will incorporate this expanded understanding of dietary influence to provide a database necessary for specific investigations into mechanisms by which an obesogenic diet compromises corneal function.Our most recent data in vivo reveal that 10 week old mice fed a high fat diet for 5 weeks show systemic inflammation with increased proinflammatory cytokines in blood as well as leukocyte activation and infiltration into adipose tissues. These mice exhibit significant reductions in nerve density in the epithelial branches of the corneal nerves, and when challenged, they exhibit abnormal wound healing after corneal abrasion with reduced regeneration of damaged corneal nerves. This extends our analysis of the inflammatory cascade activated by epithelial injury, defines corneal dysfunctions induced by an obesogenic diet, and seeks to define new targets for potential therapeutic intervention. Our most recent data in vitro reveal expression of receptors on human corneal epithelium for cytokines that in the mouse model promote epithelial healing. Specific Aim 1. Determine changes in the cornea induced by feeding mice an obesogenic diet, the reversibility of these changes, and the contributions of diet-induced systemic inflammation to these changes. Hypothesis 1: Dysregulated inflammation induced by an obesogenic diet contributes to corneal pathology. Specific Aim 2. Analyze the cascade of events required for normal corneal wound healing in mice fed an obesogenic diet that induces systemic inflammation, and determine if therapeutic intervention directed at restoring specific aspects of the healing cascade will promote efficient corneal wound healing. In addition, analyze the effects of specific interventions derived from the mouse studies on healing functions of human corneal epithelial cells in vitro. Hypothesis 2: The cascade of events required for normal corneal wound healing is disrupted by diet- induced systemic inflammation, thereby leading to poor corneal wounding healing.